KEYNOTE-045

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Bellmunt J, et al. "Pembrolizumab as second-Line therapy for advanced urothelial carcinoma". The New England Journal of Medicine. 2017. 376:1015-1026.
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Clinical Question

In patients who have failed chemotherapy treatment for advanced urothelial cancer, does treatment with Pembrolizumab provide a survival benefit?

Bottom Line

Pembrolizumab provides a benefit in terms of overall survival, but not progression free survival. In this group of patients, treatment with Pembrolizumab was associated with a lower rate of treatment related adverse effects

Major Points

Pembrolizumab is a monoclonal anti-body targeting PD-1 (Programmed cell death protein 1). PD-L1, the ligand for PD1, is highly expressed in several cancers. It is thought to down regulate the immune system. Targeting PD-1 with antibody therapies is thought to enhance an immune response against cancer cells.

In this paper, Pembrolizumab is shown to be effective in increasing overall survival in a second-line therapy for advance urothelial cell cancer, and it does so with a reduced number of adverse events compared with standard chemotherapy.

While the survival benefit provided by Pembrolizumab was small (~ three months) this is achieved in a patient group where there are few other treatment options, and with fewer adverse effects compared with chemotherapy.

Guidelines

The European Association of Urology 2017 Guidelines on Upper Tract Urothelial Cell Cancer.[1]

  • Systemic chemotherapy
    • Extrapolating from the bladder cancer literature and small, single centre UTUC studies, platinum-based combination chemotherapy is expected to be efficacious in UTUC. However, there are currently insufficient data upon which to base recommendations.
    • There are several platinum-based regimens, but not all patients can receive adjuvant chemotherapy because of comorbidities and impaired renal function after radical surgery. Chemotherapy-related toxicity, particularly nephrotoxicity from platinum derivatives, may significantly affect survival in patients with post-operative renal dysfunction.
    • There were no adverse effects of neoadjuvant chemotherapy for UTUC in the only study published to date, although survival data need to mature and longer follow-up is awaited. Adjuvant chemotherapy can achieve a recurrence-free rate of < 50%.
    • After a recent comprehensive search of studies examining the role of peri-operative chemotherapy for UTUC, there appears to be an overall survival and disease-free survival benefit for cisplatin-based adjuvant chemotherapy(LE: 3). However, there are currently insufficient data to base recommendations on until further evidence from an ongoing prospective trial is available.

Design

  • Trial type: international, randomized, open-label, phase 3
  • N=number of patients randomized (often different from number of patients enrolled)
    • Experimental arm: 270
    • Standard: 272
  • Setting: 120 sites, 29 countries
  • Enrolment: November 5 2014-November 13 2015
  • Median follow-up: 14.1 months (range, 9.9 to 22.1).
  • Analysis: main analysis type: Efficacy analysis – intention to treat; safety analysis – as treated.
  • Primary outcome: “co-primary endpoints” were described as overall survival and progression free survival.

Population

Inclusion Criteria

  • 18 years of age or older
  • Histologically or cytologically confirmed urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra that showed predominantly transitional-cell features on histologic testing,
  • Progression after platinum-based chemotherapy for advanced disease or recurrence within 12 months after the receipt of platinum-based adjuvant or neoadjuvant therapy for localized muscle-invasive disease, had received two or fewer lines of systemic chemotherapy for advanced disease previously,
  • At least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1,15 and had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2 (on a 5-point scale, with 0 indicating no symptoms and higher numbers indicating greater disability).

Exclusion Criteria

  • Patients who had an ECOG performance-status score of 2 (indicating that the patient is ambulatory and capable of all self-care but is unable to carry out any work activities and is out of bed more than 50% of waking hours) and had one or more of the established poor prognostic factors for second-line therapy (i.e., hemoglobin concentration of <10 g per deciliter, presence of liver metastases, and receipt of the last dose of most recent chemotherapy <3 months before enrollment) were excluded from enrollment.
  • Patients were ineligible if they had received anti–PD-1, anti–PD-L1, or anti–CTLA-4 therapy previously.

Baseline Characteristics

Baseline characteristics were similar between the two groups of this study. For the treatment group:

  • The average age at enrolment was 67 years
  • 74% were male
  • 44.1% had and ECOG status of 0, 53% ECOG 1, 0.7 ECOG 2
  • 61.3% were current or former smokers
  • 68.9% had pure transitional-cell features on histologic testing
  • 28.5% had a tumour PD-L1 combined positive score of >=10%
  • 85.9% had the primary tumour in the bladder or urethra
  • 89.2% had visceral disease
  • 33.7% had liver metastases
  • 16.4% had haemoglobin <10
  • 20% - 0 risk factors, 35.6% - 1 risk factor, 24.4% - 2 risk factors, 16.7% - 3 or 4 risk factors
  • 38.3% completed or discontinued their ,most recent therapy in less than three months previous

Interventions

  • Patients were randomly assigned in a 1:1 ratio to a group:
    • Pembrolizumab - 200 mg
    • Chemotherapy - Investigator’s choice of paclitaxel (at a dose of 175 mg per square meter of body-surface area), docetaxel (at a dose of 75 mg per square meter), or vinflunine (at a dose of 320 mg per square meter), all administered intravenously every 3 weeks.
  • Randomization was stratified according to ECOG performance-status score (0 or 1 vs. 2), presence of liver metastases (yes vs. no), hemoglobin concentration (<10 g per deciliter vs. ≥10 g per deciliter), and time since the last dose of chemotherapy (<3 months vs. ≥3 months).
  • Treatment assignment was not blinded.
  • Treatment was continued until RECIST-defined disease progression, development of an unacceptable level of toxic effects, withdrawal of consent, decision by the investigator to discontinue treatment, or the completion of 2 years of pembrolizumab therapy.

Outcomes

Primary Outcomes

Overall survival
Significantly longer in the pembrolizumab group than in the chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.59 to 0.91; P = 0.002)
PFS
437 events of disease progression or death occurred in the intention-to-treat population, with no significant difference in the duration PFS between the pembrolizumab group and the chemotherapy group (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P = 0.42)

Secondary Outcomes

Adverse events
60.9% of pembrolizumab patients and 90.2% of chemotherapy patients.
Objective response rate
Per RECIST 1.1. by independent radiologists’ review in subjects with recurrent/progressive metastatic urothelial cancer treated with pembrolizumab (MK-3475) compared to paclitaxel or vinflunine.
Pembrolizumab achieved an objective response rate of 21.1%, 95% CI 16.4-26.5, while chemotherapy achieved an objective response rate of 1.4%, 95% CI 7.9-15.8. (p=0.001).

Subgroup Analysis

The most clinically relevant subgroup analysis in this study is the evaluation of patients with >=10% PD-L1 (Programmed death-ligand 1) tumour markers. Overall survival was significantly better in this subgroup compared with chemotherapy patients (HR 0.57, 95% CI 0.37-0.88, p=0.005).

Adverse Events

Overall events
60.9% of patients in the pembrolizumab vs. 90.2% in the chemotherapy group
Leading to death
1.5% in the pembrolizumab, 1.6% in the standard chemotherapy
Leading to discontinuation
5.6% in the pembrolizumab group and 11.0% in the chemotherapy group.
Pruritis
19.5% of patients in the pembrolizumab group vs. 2.7% in the chemotherapy group
Alopecia
0% in pembrolizumab vs. 37.8% in the chemotherapy group.

Criticisms

  • The survival curves cross one another, suggesting that proportional hazards assumption was violated and the Cox proportional hazards model may not be the appropriate statistical method.
  • Health economics is likely to play a key role in determining uptake as pembrolizumab is expensive.

Funding

Merck (Kenilworth, NJ)

Further Reading

  1. Rouprêt M et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. Eur. Urol. 2018. 73:111-122.